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Lookup NU author(s): Professor Ruth PlummerORCiD
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©2025 American Association for Cancer Research.In this phase Ib basket expansion trial and alternative-schedule dose-escalation study, we evaluated the ataxia-telangiectasia and rad3-related (ATR) inhibitor elimusertib at 40 mg twice daily (3 days on/4 days off) in 143 patients with advanced cancer with tumor-associated DNA damage response defects, comprising gynecologic (n = 45), prostate (n = 19), colorectal (n = 24), and breast (n = 19) cancer, and ataxia-telangiectasia-mutated (ATM) loss (n = 36). An alternative schedule (3 days on/11 days off) was assessed in patients with ATM loss and/or ATM mutations (n = 32). Elimusertib-related reversible hematologic toxicities were observed. Objective responses were modest (4.5%), but a disease control rate (DCR) of 49.3% indicated that subpopulations of patients, especially those with gynecologic cancers (DCR 59.5%), derived meaningful, durable benefits from elimusertib. There was no association between ATM protein loss or ATM alterations and progression-free survival or overall response. Further studies to define optimal predictive biomarkers for ATR inhibitors, both as monotherapy and in combination, are ongoing. SIGNIFICANCE: This is the largest ATR inhibitor monotherapy study reported to date. A DCR of 49.3% indicated that subpopulations of patients, especially those with gynecologic cancers (DCR 59.5%), derived meaningful benefits from elimusertib. Biomarker studies suggest that early ctDNA response may potentially predict clinical benefit from ATR inhibitors.
Author(s): Yap TA, Tan DSP, Stathis A, Shapiro GI, Iwasa S, Joerger M, Zhang J, Plummer R, Sawyer MB, Tan DSW, Castonguay V, Gabrail NY, Matsubara N, Wilkinson G, Ludwig M, Schlicker A, Zhou Y, Merz C, Dabritz JHM, Jeffers M, Hreiki J, de Bono JS
Publication type: Article
Publication status: Published
Journal: Cancer Discovery
Year: 2025
Volume: 15
Issue: 10
Pages: 2019-2035
Print publication date: 01/10/2025
Online publication date: 06/10/2025
Acceptance date: 12/06/2025
ISSN (print): 2159-8274
ISSN (electronic): 2159-8290
Publisher: American Association for Cancer Research
URL: https://doi.org/10.1158/2159-8290.CD-24-1500
DOI: 10.1158/2159-8290.CD-24-1500
PubMed id: 40516108
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